Animal pharming is the process of using transgenic animals to produce human drugs, mostly in the mammary glands of female animals. The US Food and Drug Administration (FDA) issued its first approval for ATryn, the recombinant human antithrombin III, produced in the milk of transgenic goats in 2009. Prior to FDA approval, this drug gained the approval by the European Medicines Agency in 2006. Another drug, Ruconest, produced in the milk of rabbits was approved in Europe in 2011. Because of the increasing global demand for human proteins and vaccines, the decreasing volume of donated blood especially in developing countries, and the fact that animal bioreactors can significantly reduce the unit cost per protein by as much as ten folds comparing to the traditional cell culture based method, it is important to continue exploring and improving the animal pharming technologies. There are mainly two methods to produce transgenic pharming animals, namely pronuclear DNA microinjection and nuclear transfer. The first one, pronuclear microinjection, suffers from problems such as random copy numbers and insertion sites of the transgene, unpredictable level of the transgene expression, and generally low transgenic rates. The second one, nuclear transfer, can only be applied to animals that can be cloned efficiently such as cattle, pigs, and goats, but not to other species such as rabbits. Furthermore, nuclear transfer suffers from low rates of healthy live births. Here we propose to modernize, streamline, and possibly standardize the 30-yr old animal pharming technology by integrating the emerging gene targeting technologies, the recently available whole genome sequence information of rabbits, and our expertise in rabbit embryology and transgenics. We propose to use Cas9 based RNA Guided Endonucleases(RGEN) or Transcription Activator-like Effector Nuclease (TALEN) to facilitate the knock in of a transgene at the locus of one major rabbit milk protein gene (i.e. beta-casein). We further propose to introduce docking sites (attP) flanking the transgene, enabling modularized insertion of new transgene(s) between the docking sites mediated by the integrase system in a cassette exchange manner with high knock- in efficiency. This new system will bring the following improvements to the current pharming technologies: (i) a more reliable expression system that takes the advantage of the promoter of an endogenous major milk protein, resulting in elevated recombinant protein yield up to the level of 10 g/L; (ii) a modularized system that can be used for streamlined production of many other recombinant proteins; and (iii) a standardized production system for different biologicals of interests with known insertion site and copy number of the transgene, and predictable expression level of the product. More importantly this system can be readily adapted for other large animal species such as pigs and cattle.